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Immediate and Delayed Effects of E-Cadherin Inhibition on Gene Regulation and Cell Motility in Human Epidermoid Carcinoma Cells

Henriette Andersen,^2, Jakob Mejlvang,^1, Shaukat Mahmood,² Irina Gromova,³ Pavel Gromov,³ Eugene Lukanidin,² Marina Kriajevska,¹ J. Kilian Mellon,¹ and Eugene Tulchinsky^1*

Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom,¹ Department of Molecular Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen 2100, Denmark,² Department of Proteomics in Cancer, Danish Cancer Society, Strandboulevarden 49, Copenhagen 2100, Denmark³

Received 1 March 2005/ Returned for modification 8 April 2005/ Accepted 21 July 2005

The invasion suppressor protein, E-cadherin, plays a central role in epithelial cell-cell adhesion. Loss of E-cadherin expression or function in various tumors of epithelial origin is associated with a more invasive phenotype. In this study, by expressing a dominant-negative mutant of E-cadherin (Ec1WVM) in A431 cells, we demonstrated that specific inhibition of E-cadherin-dependent cell-cell adhesion led to the genetic reprogramming of tumor cells. In particular, prolonged inhibition of cell-cell adhesion activated expression of vimentin and repressed cytokeratins, suggesting that the effects of Ec1WVM can be classified as epithelial-mesenchymal transition. Both short-term and prolonged expression of Ec1WVM resulted in morphological transformation and increased cell migration though to different extents. Short-term expression of Ec1WVM up-regulated two AP-1 family members, c-jun and fra-1, but was insufficient to induce complete mesenchymal transition. AP-1 activity induced by the short-term expression of Ec1WVM was required for transcriptional up-regulation of AP-1 family members and down-regulation of two other Ec1WVM-responsive genes, S100A4 and igfbp-3. Using a dominant-negative mutant of c-Jun (TAM67) and RNA interference-mediated silencing of c-Jun and Fra-1, we demonstrated that AP-1 was required for cell motility stimulated by the expression of Ec1WVM. In contrast, Ec1WVM-mediated changes in cell morphology were AP-1-independent. Our data suggest that mesenchymal transition induced by prolonged functional inhibition of E-cadherin is a slow and gradual process. At the initial step of this process, Ec1WVM triggers a positive autoregulatory mechanism that increases AP-1 activity. Activated AP-1 in turn contributes to Ec1WVM-mediated effects on gene expression and tumor cell motility. These data provide novel insight into the tumor suppressor function of E-cadherin.

H.A. and J.M. contributed equally to this work.

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